The oncogenic human herpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are the causative agents of multiple malignancies. A hallmark of herpesviruses is their biphasic life cycle consisting of latent and lytic infection. In this study, we identified that cellular nonsense-mediated decay (NMD), an evolutionarily conserved RNA degradation pathway, critically regulates the latent-to-lytic switch of EBV and KSHV infection. The NMD machinery suppresses EBV and KSHV Rta transactivator expression and promotes maintenance of viral latency by targeting the viral polycistronic transactivator transcripts for degradation through the recognition of features in their 3' UTRs. Treatment with a small-molecule NMD inhibitor potently induced reactivation in a variety of EBV- and KSHV-infected cell types. In conclusion, our results identify NMD as an important host process that controls oncogenic herpesvirus reactivation, which may be targeted for the therapeutic induction of lytic reactivation and the eradication of tumor cells.